Solid Sources of Carbon Monoxide

Solid Sources of Carbon Monoxide as Safe Reagents in Process Chemistry – Equipment, Handling and Isotope Labelling

The Danish Council for Independent Research | Technologi and Production - Grant: DKK 5,033,441

Project Period: 01.01.2013 - 31.12.2016

 

Project Description

 

The Aim: It is our goal to develop a simple and safe method for the application of harmful gasses, such as carbon monoxide, on laboratory scale. By applying a gas-precursor, in the form of a stable and manageable solid, this approach provides a direct alternative to the use of pressurized cylinders. The developed technique will, not only, solve the safety issues when working with toxic and flammable gasses but also provide a link between laboratory scale and bulk production of fine chemicals. Furthermore, the technology developed will be adapted to new methods for isotope-labelling, which is mandatory for the safety assessment of new pharmaceuticals and agrochemicals.

 

Introduction and background: Carbon monoxide is an important reagent for the chemical industry for the synthesis of fine chemicals, pharmaceuticals and agrochemicals. The downside of using CO is nevertheless its high toxicity. Furthermore, this gas is flammable, colourless, odourless and without taste, and hence extreme caution must be taken in its handling. This includes the use of specialised equipment, safety laboratories and the use of gas-detectors. Until now, equipment such as autoclaves are applied, capable of handling the dangerous gas at high temperatures and pressures. For small-scale purposes in research and academia, carbon monoxide is often avoided due to the obvious safety concerns. These problems only expand, when chemical companies require the scale-up of these reactions. Only a limited number of Research & Development (R&D) laboratories possess the appropriate equipment for scale-up production and often the problem is solved by buying this service either as an “in-house”-production at a remote site or via an external contract research organisation (CRO). Both of these approaches results in the loss of throughput and flexibility slowing the overall progress of a given project.

In the commercialisation of new pharmaceuticals and agrochemicals, governmental agencies (f. ex. European Medicines Agency for Pharmaceuticals, European Environment Agency for Agrochemicals) require that such chemicals must undergo a range of distribution and degradation studies in order to determine unforeseen health and environmental risks. Such studies are done with isotopically labelled chemicals both cold and hot.

In this research proposal, we address these problems of working with this dangerous but synthetically and industrially important gas. We propose solutions for the safe management of reactions, which require carbon monoxide as a reagent on a laboratory and medium size scale for R&D laboratories, and we also provide a viable solution for performing reactions with isotope-labelling with isotopically-labelled carbon monoxide. Finally, we will also adapt this protocol to other dangerous gasses.

 

Project Outline and Research Plan: We have recently reported the development of two new carbon monoxide precursors, which represent easy, and highly manageable crystalline solids, and which are capable of releasing the gas in a controlled and safe fashion (P. Hermange, T. Skrydstrup et al., J. Am. Chem. Soc. 2011, 133, 6061; S. Friis, T. Skrydstrup et al., J. Am. Chem. Soc. 2011, 133, 18114). In combination with a two-chamber glassware system, the produced CO was incorporated into a variety of molecular structures with high efficiency. Furthermore, we were able to design reaction conditions, which used only stoichiometric amounts of CO, which clearly diminishes the safety issues of such reactions. This work was highlighted in Chemical & Engineering News (Issue of April 11th, 2011) from the American Chemical Society as a safe new way of working with carbon monoxide (Borman 2011). To further extend this work we will examine its possibilities for scale-up (Work packages 1 and 2) and as a viable means for isotopically labelling pharmaceuticals and agrochemicals (Work package 3). Finally, as an extension of this methodology, we are interested in extending this technology to other gasses such as sulphur dioxide (SO2) and ethylene, which may also be a very useful gas for the construction of important industrial chemicals.

 

Work package 1 (WP1): Safe production of CO for scale-up purposes: In order to perform carbonylation chemistry (reactions with CO) on large scale, the development of protocols, which allow chemists to produce CO continuously in a safe and highly controllable manner, would be required. Based on the already known CO-precursors several intrinsic factors of the palladium catalysed CO-release will be investigated as stated below:

  1. Portion wise addition of key components of the CO-releasing reaction providing an on/off switch by halting the reaction upon depletion of the limiting reagent. CO-production will resume upon renewed addition of substrate.
  2. Continuous CO-production could be set to a fixed rate by regulating the catalytic loading, the reaction temperature or by continuous addition of limiting substrate in a similar manner as in WP1-1. Ultimately, such a design, in which the CO-producing reaction and the CO-consuming reaction are operating at the same rates, could be identified.
  3. In carbonylation chemistry it is a well-known fact that high concentrations of CO leads to formation of inactive CO-catalyst clusters. An initial faster CO-production compared to the CO-consumption would lead to a similar situation thereby slowing the palladium catalysed CO-generation. This feed-back control will ultimately lead to a steady state situation where CO-generation follows CO-consumption at a partial pressure of CO, which depends on the conditions for CO-generation. Hence, a pressure build-up is prevented, resulting in a safe application of CO.

 

Work package 2 (WP2): Flexible equipment for large-scale carbonylations: The intended idea of this work package is to develop a flexible equipment for carbonylation chemistry which fits into any fumehood. The basic outline is an adaptor connecting the CO-producing and the CO-consuming chamber. The design would be based on commercially available glassware ensuring access to a large variety in the desired reaction vessels. The adaptor will consist of a connector unit, a pressure gauge for online monitoring of the total pressure in the reaction setup, and finally, in and outlets for evacuation and addition of reagents as mentioned in WP1. The ideal solution should be adaptable to all reaction scales ranging from 1 - 50 grams of isolated product only requiring change in the size of the applied reaction vessels. The intended outcome of WP2 would become an all-purpose tool for the organic chemist, potentially adaptable to other gasses than CO.

 

Work Packages 3 (WP3): Carbon isotope labelling: In this part of the research proposal we will attempt to apply our developed technique towards a solution addressing the problems associated with handling of the radioactive gas [14C]-CO. The following subjects will be investigated.

  1. Production of [14C]-CO under controlled conditions and in the exact amount desired. All [14C]-isotope originates from [14C]-CO2 and this should be used as our source of the carbon isotope by trapping and transformation into a stable [14C]-CO. [14C]-CO release from these precursors would then provide access to carbonylation chemistry.
  2. Disposal of radioactive waste in [14C]-labelling is an extensive and very costly problem. Application of [14C]-CO addresses this problem directly producing a minimum of waste while simultaneously allowing the isotope to enter the target molecule in an advanced intermediate eliminating further waste producing steps from the linear sequence
  3. Venting of [14C]-CO, being a radioactive gas, is prohibited in general. Hence, if the presented technology is to be applicable the development of a scrubber, capable of trapping any remaining [14C]-CO, would be mandatory.

 

Work Packages 4 (WP4): Safe handling of other harmful gasses: In this work package we will attempt to transfer the gained knowledge from the WP1-WP3 to other synthetically useful but harmful gasses. Especially, the generation of sulphur dioxide (SO2) will be investigated since this molecule holds similar intrinsic properties to that of CO. Potential products from the application of SO2, such as sulphuryl amides, are general motifs in many biologically active compounds including agrochemicals. Other gasses which can be examined include ethylene, which is an important but flammable gas for fine chemical production.

 

Project Outcome: The results from the suggested projects would result in a new way of implementing small gaseous reagents into the development and production of chemical compounds and in new technical solutions for applying gasses in chemical reactions. Successful identification of solid precursors of reactive and toxic gases and technical solutions for the application of such precursors in laboratory scale chemical reactions, could provide the chemical industry with a simple link between R&D and production, thus enabling production to take direct advantage of the synthetic knowledge from R&D as opposed to redesigning synthetic routes.

 

List of participants in the project

Troels Skrydstrup (iNANO and Department of Chemistry)

Anders Lindhardt (iNANO and Department of Engineering)

Rolf Taaning (iNANO and Department of Chemistry)

Thomas Andersen (iNANO and Department of Chemistry)